1. Field of Invention
The invention relates to cellulosic dialysis membranes, methods for their manufacture, and their use especially for hemodialysis, hemofiltration, and hemodiafiltration, with the term "cellulosic" meaning: consisting of cellulose or modified cellulose, mixtures of cellulose and modified cellulose, possibly mixed with synthetic polymers.
2. Discussion of Related Art
Dialysis membranes made of synthetic or natural polymers can very easily cause blood to clot when used in artificial kidneys, but this can be largely prevented by suitable drug treatment.
When a kidney patient receives dialysis treatment using dialyzers that contain membranes made of regenerated cellulose, a temporary drop in the white blood cell count takes place during the initial phase of dialysis treatment. This effect is termed leukopenia.
Leukopenia is a drop in the number of leukocytes (white blood cells) in the bloodstream. The number of white blood cells in humans is approximately 4000 to 12,000 cell/m.sup.3. Leukopenia is most pronounced 15 to 20 minutes after dialysis treatment begins, and the neutrophils can disappear almost completely. The number of leukocytes then recovers within about 1 hour and returns to almost the initial value, or exceeds it. When a fresh dialyzer is connected after the leukocytes recover, leukopenia recurs to the same degree.
Cellulose membranes cause pronounced leukopenia. Although the clinical significance of leukopenia has not yet been scientifically clarified, there is a desire to have a dialysis membrane for hemodialysis that does not display the effect of leukopenia without the other highly desirable positive properties of dialysis membranes made of regenerated cellulose being adversely affected as a result.
When hemodialysis is performed using membranes made of regenerated cellulose, manufactured by the cuprammonium method, definite complement activation has also been found in addition to the leukopenia. The complement system within the blood serum is a complex plasma enzyme system consisting of many components that serves to defend against injury caused by invading foreign cells (bacteria and the like) in different ways. If antibodies against structures on the foreign surface are present, the complement system can be activated in the classical fashion; otherwise complement activation takes place in an alternative pathway through special features of the foreign surface. The complement system consists of a plurality of plasma proteins. Following activation, these proteins react with one another specifically in a certain sequence and eventually a cell-damaging complex is formed that destroys the foreign cell.
Peptides are released from individual components that trigger the inflammation phenomena and can sometimes also have undesired pathological consequences for the organism. It is assumed that the activation in hemodialysis membranes made of regenerated cellulose takes place via the alternative pathway. These complement activations are determined objectively by determining the complement fragments C.sub.3a and C.sub.5a.
In this connection, reference will now be made to the following articles: D. E. Chenoweth et al., Kidney International, Vol. 24, p. 764 et seq., 1983 and D. E. Chenoweth, Asaio-Journal, Vol. 7, p. 44 et seq., 1984.
Complement activation is judged by the measurement of the C.sub.5a fragments within the scope of the present invention. For this purpose, 300 ml of heparinized blood is recirculated in vitro for a period of 3 hours at a flowrate of 250 ml per minute through a dialyzer with 1-1.3 m.sup.2 effective exchange area. The C.sub.5a fragments are determined in the blood plasma with the aid of the ELISA method developed by Behring, Marburg (enzyme linked immunosorbent assay). The relative complement activation for the respective measuring time is calculated from the ratio of the concentration at the time the sample is collected to the concentration at the beginning in percent. The measured value after 3 hours recirculation time is used for evaluation. Flat membranes are incubated with heparinized blood plasma for 3 hours and the C.sub.5a fragments are then determined.
Thrombogenesis is evaluated on the basis of TAT (thrombin-antithrombin) and PC (platelet count).
An increase in the beta-2-microglobulin level is observed in long-term dialysis patients following the use of membranes made from regenerated cellulose and is attributed to the fact that these membranes are less permeable in the molecular weight range from 1000 to 20,000 and the microglobulins therefore are not removed to a sufficient extent during dialysis. The beta-2-microglobulin is not adsorbed to a significant degree on conventional membranes made of regenerated cellulose. For this purpose however the cellulose derivatives used according to the invention can make an unanticipated contribution.
The average degree of polymerization (DP) of the cellulose is determined in a copper ethylenediamine solution according to DIN 54270.
The degree of modification or substitution (DS) is determined on the basis of analyses that are known for the substituents and are typical, for example nitrogen according to Kjeldahl, sulfur according to Schoniger, and alkyl or aryl residues using NMR, UV, NIR, IR or Raman spectroscopy.
It is also found that it is desirable to avoid thrombogenesis and heparin adsorption.
Increasingly demanding requirements are being imposed on cellulosic dialysis membranes which are intended to be used for hemodialysis in particular. Thus the membrane must be biocompatible, in other words especially compatible with blood. The complement activation should be as low as possible and the membrane should not exhibit any thrombogenesis. Moreover there is a desire to have cellulosic dialysis membranes available whose ultrafiltration rate (UFR) and screening coefficients can be adjusted for individual applications. Of particular interest in this regard are the so-called "low flux," "middle flux," and "high flux" ranges. In addition the membranes should be resistant to aging, in other words not change their properties when stored; they should be sterilizable using known methods such as steam, ethylene oxide, and radiation treatment. In addition, there is also interest in manufacturing methods that are environmentally safe and can be performed economically, in other words methods in which the environment is not endangered by the disposal of chemicals and which permit high productivity, especially a high production rate.
Important criteria for evaluating the performance of a dialysis membrane are the ultrafiltration rate (UFR) and the screening coefficient (SK).
The ultrafiltration rate is defined as the permeate volume that passes through the membrane wall per unit time, as a function of the membrane area and test pressure (equation 1): ##EQU1## V=fluid volume (permeate) [ml]t=time [h]
A=membrane area [m.sup.2 ] PA1 p=test pressure [mm Hg]
In the case of porous membranes, the separating properties are determined primarily by the pore size. Small molecules, for example urea, can pass with almost no resistance through the membrane wall, medium-sized molecules for example cytochrome C, beta-2-microglobulin, can pass through to a certain percentage, and large molecules, for example albumin, can practically not pass through at all. Hence the characterization of membrane separating properties relies on the determination of the screening coefficients of particle types of different sizes in an ultrafiltration experiment and is defined as the ratio of the concentrations in the filtrate and the stock solution (Equation 2) ##EQU2## C.sub.F =concentration of the particle type in question in the filtrate C.sub.St =concentration of the particle type in question in the stock solution.
The classic (and still much in use today) method for making cellulosic dialysis membranes is based on the so-called cuprammonium method.
This method permits only a low production rate and these membranes, because of their dense structure, are generally suitable only for the so-called "low flux" range. In addition these membranes age very rapidly. Moreover, according to the cuprammonium method, a number of modified cellulose and/or cellulose derivatives as well as mixtures with synthetic polymers can be processed very poorly if at all.
In addition, the recovery of the chemicals that are used in this method such as ammonia and basic copper sulfate is costly. In addition, there is a significant salt burden, such as sodium sulfate and ammonium sulfate.
Methods have also been described in which such chemicals are not used. DE-C2-3 021 943 discloses a method for making a dialysis membrane out of cellulose in which a spinning solution is made from a mixture of cellulose, a tertiary amine oxide as well as (possibly) diluents that do not dissolve the cellulose and other conventional additives, and this is extruded through a spinneret into a regenerating bath. A dialysis membrane thus forms by coagulation, and must still be washed and dried and wound after adding softeners to prevent shrinkage between 50 and 110.degree. C.
This method however has low productivity; the takeoff speed is very low and there are no specific instructions as to how the pore structure can be influenced and in particular how membranes can be produced that meet the requirements for the low, middle, or high flux ranges. There are also problems with finishing, as will be discussed below. The regenerating bath temperature must also be kept low since otherwise the performance in dialysis is reduced.
The membranes have a very dense structure whose ultrafiltration rate is very low so that they can be used only as so-called "low flux" membranes.
These membranes must be kept in moisture-tight containers since they have a very labile structure and very quickly undergo irreversible structural changes.
Although many methods for making cellulosic membranes are already known, there is still a need for an improved method for making them, including a method for making cellulosic membranes with good or improved properties as well as for making membranes for the low, middle, and high flux ranges.